CN106317172A - Pro-Ser, and synthesis, activity and application thereof - Google Patents
Pro-Ser, and synthesis, activity and application thereof Download PDFInfo
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- CN106317172A CN106317172A CN201510351774.3A CN201510351774A CN106317172A CN 106317172 A CN106317172 A CN 106317172A CN 201510351774 A CN201510351774 A CN 201510351774A CN 106317172 A CN106317172 A CN 106317172A
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Abstract
The invention discloses Pro-Ser, a preparation method, analgesic activity, anti-inflammatory activity, antitumor activity and thrombolysis activity of Pro-Ser, and application of Pro-Ser to preparation of analgesic drugs, anti-inflammatory drugs, antitumor drugs and thrombolysis drugs.
Description
Technical field
The present invention relates to Pro-Ser, relate to its preparation method, relate to its analgesic activity, relate to its antiinflammatory action,
Relate to its antitumor action, relate to its antithrombotic acitivity and relate to its thrombus dissolving activity, thus the present invention relates to
Its application in preparing analgesic, anti-inflammatory drug, antitumor drug and thrombolytic agent.The invention belongs to biology
Field of medicaments.
Background technology
Invention antitumor, antithrombotic, thrombus dissolving, anticoagulation and analgesic activity oligopeptide are the fields that inventor pays close attention to for a long time.
Although the most a series of oligopeptide with these activity of inventor's disclosure of the invention, but integrate the oligopeptide one of these activity
Directly do not obtain.Inventor finds, Pro-Ser is collection analgesic activity, antiinflammatory action, antitumor action and thrombus dissolving
It act as the oligopeptide of one.Realize according to this, inventors herein propose the present invention.
Summary of the invention
First content of the present invention is to provide Pro-Ser
Second content of the present invention is to provide the synthetic method of Pro-Ser, and the method includes:
(1) under the catalysis of DCC, HOBt, Boc-Pro-Ser-OBzl is prepared；
(2) Boc-Pro-Ser-OBzl is in hydrogen chloride-ethyl acetate solution that concentration is 4N, and 0 DEG C of de-Boc changes into
Pro-Ser-OBzl；
(3) Pro-Ser-OBzl is at H2Pro-Ser is prepared under Pd/C catalysis；
3rd content of the present invention is to evaluate the analgesic activity of Pro-Ser.
4th content of the present invention is to evaluate the antiinflammatory action of Pro-Ser.
5th content of the present invention is to evaluate the antitumor action of Pro-Ser.
6th content of the present invention is to evaluate Pro-Ser thrombus dissolving effect.
Accompanying drawing explanation
Synthetic route .i of Fig. 1 .Pro-Ser) dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine
(NMM), oxolane (THF)；Ii) 4N hydrogen chloride-ethyl acetate solution, 0 DEG C；iii)H2, Pd/C.
Detailed description of the invention
In order to the present invention is expanded on further, a series of embodiment is given below.These embodiments are entirely illustrative,
They are only used for being specifically described the present invention, are not construed as limitation of the present invention.
Embodiment 1 prepares the preparation of Boc-Pro-Ser-OBzl
Under ice bath, 2.15g (10mmol) Boc-Pro is dissolved in a small amount of anhydrous tetrahydro furan (THF), adds 1.36g
(10mmol) HOBt, adds the solution of 2.47g (12mmol) DCC and a small amount of anhydrous THF, activates 30 minutes,
Adding 1.95g (10mmol) Ser-OBzl, regulate pH=9 with NMM, reaction is filtered to remove dicyclohexyl after terminating
Urea (DCU).Filtrate reduced in volume, residue with Ethyl acetate dissolves, again filters DCU, filtrate NaHCO3
Saturated solution is washed 3 times, washes 3 times with NaCl saturated solution, the KHSO of 5%4Solution washes 3 times, and NaCl is saturated molten
Liquid is washed 3 times, the NaHCO of 5%3Solution extraction is washed 3 times, and NaCl saturated solution extraction is washed 3 times, ethyl acetate layer nothing
Water Na2SO4It is dried 12 hours, filters Na2SO4, filtrate reduced in volume, obtain 3.45g (88%) title compound,
For colourless powder.ESI+-MS (m/e): 393 [M+H]+；1H-NMR (300MHz, DMSO-d6):
δ/ppm=8.20 (d, J=7.5Hz, 1H), 7.35 (m, 5H), 5.12 (s, 2H), 4.39 (m, 1H), 4.16 (dd, J=8.4Hz,
J=11.1Hz, 1H), 3.76 (m, 1H), 3.62 (m, 1H), 3.29 (m, 2H), 2.04 (m, 1H), 1.70 (m, 3H), 1.34 (s,
9H)。
Embodiment 2 prepares the preparation of Boc-Pro-Ser
The Boc-Pro-Ser-OBzl of 3.92g (10mmol) methanol is dissolved, the Pd/C of the 10% of addition 390.Even
Connect threeway, after decompression extracts the air in eggplant bottle, reaction bulb is full of H2, is repeated 3 times by this operation.After reaction 20h
Raw material point disappears.Filtering Pd/C, filtrate reduced in volume obtains 2.95g (99%) title compound, for colourless powder.
ESI-MS (m/e): 303 [M+H]+。
Embodiment 3 prepares the preparation of Pro-Ser
Under ice bath, 3.02g (10mmol) Boc-PS-OBzl is used up the most dried acetic acid ethyl dissolution, stirring
10min, adds 3mL hydrogen chloride-ethyl acetate solution (4N) reaction 4h, and raw material point disappears.Reactant mixture subtracts
Pressure is concentrated to dryness, and residue adds the acetic acid ethyl dissolution that 40mL is dried, and the solution decompression obtained is concentrated to dryness.Residual
Thing is stayed to be repeated 3 times by this operation.Residue adds absolute ether, grinds with plastic spatula, and concentrating under reduced pressure removes ether.Residual
Thing is stayed to be repeated 3 times by this operation.Obtain 1.9g (97%) title compound, for colourless powder.ESI-MS (m/e): 203
[M+H]+；Mp 104.2～143.1 DEG C.(c=0.14, methanol).1H-NMR (300MHz,
DMSO-d6): δ/ppm=8.94 (d, J=7.2Hz, 1H), 4.27 (m, 2H), 3.71 (m, 2H), 3.23 (m, 2H), 2.33 (d,
J=7.2Hz, 1H), 1.87 (s, 3H).
Embodiment 4 evaluates the analgesic activities of Pro-Ser
Male ICR mouse (20 ± 2g) installs in mouse fixing device, and rat-tail is exposed to outside holder, in rat-tail distance tail
Labelling at point 1/3rd, as the induction point of light sensation sensor, irradiates the position of rat-tail distance tail point 2/3rds.
Dolorimeter preheating 30min, clocks, mice rat-tail is covered light sensation instrument.Starting to clock during lamp flicker, rat-tail leaves light
Stopping clocking during sense instrument, the time recorded is mice and produces the time of pain, METHOD FOR CONTINUOUS DETERMINATION 3 times, each measurement interval
For 5min, average.Keenly feel the time based on the time that mice of not taking medicine produces pain.The mice caused of taking medicine produces
Raw pain time change reflects the analgesic activities of medicine.Mice, random packet, often group 14, measure basis pain
After time, mice or the normal saline solution of oral 0.2mL Pro-Ser (PS), dosage is 1 μm ol/kg or oral 0.2mL
Normal saline or the normal saline solution of oral aspirin, dosage is 1200 μm ol/kg.Measure be administered after 30,60,90,
120,150 and 180min mices produce the time of pain.The data mean value ± SD second represents, arranges such as table 1, uses variance analysis
And carry out t inspection.Data show, oral normal saline 30,60, and after 90,120,150 and 180min, mice produces pain
The basic pain time before time and the oral normal saline of sense is not significantly different from；Oral 1200 μm ol/kg Ah Sis
After woods 60,90,120,150 and 180min, mice produces before time of pain is considerably longer than oral aspirin
The basis pain time；After oral 1 μm ol/kgPro-Ser 30,60,90,120,150 and 180min, mice produces pain
Time be considerably longer than the basic pain time before oral Pro-Ser.The most visible, oral 1 μm ol/kgPro-Ser60,
Analgesic activities after 90,120,150min is suitable with oral 1200 μm ol/kg aspirin.And be administered orally
Analgesic activities after 1 μm ol/kgPro-Ser 30min is stronger than oral 1200 μm ol/kg aspirin.
The analgesic activities of table 1Pro-Ser
N=14；A) with the basis pain time than p ＞ 0.05；B) with the basis pain time than p ＜ 0.05；C) with basis pain time ratio
P ＜ 0.05.
Embodiment 5 evaluates the anti-inflammatory activity of Pro-Ser
Body weight 20 ± male mice is administered orally 1 μm ol/kg Pro-Ser or 1200 μm ol/kg aspirin or 0.2mL/20g
After normal saline 30 minutes, the left ear gabarit toward white mice is coated with dimethylbenzene (0.04mL), by white mice cervical vertebra after 2 hours
Dislocation is put to death.By a left side for mice, auris dextra is cut, and with the card punch of diameter 7mm in the same position of two ears, takes circle
Shape auricle, weighs respectively, obtains the weight difference of two circle auricles as swelling.(swelling=former of left ear weight-right side
Former weight of ear) activity of compound is represented with swelling.This experimental data statistics all uses t inspection and variance analysis,
Swelling with () represent.Result shows, Mus ear swelling degree tool compared with normal saline group of Pro-Ser treatment
There is significant difference, show that compound has definite anti-inflammatory activity.
The anti-inflammatory activity of table 2Pro-Ser
N=14；A) with normal saline group than p ＜ 0.01.
Embodiment 6 evaluates the anti-tumor activity of Pro-Ser
Take under aseptic condition and be inoculated in the ICR mice S180 sarcoma of 7-10 days, add appropriate normal saline tumor cells
Suspension, cell number is 2 × 107/ mL, is inoculated in healthy male ICR mouse forelimb axil subcutaneous, every injected in mice 0.2mL.
After tumor inoculation 24h, the normal saline solution of mice lumbar injection every day 0.2mL Pro-Ser, successive administration 10 days,
Dosage is 1 μm ol/kg；Or the normal saline solution of mice lumbar injection every day 0.2mL amycin, successive administration 10 days,
Dosage is 2 μm ol/kg；Or mice lumbar injection every day 0.2mL normal saline, successive administration 10 days.Experiment carry out to
11st day, claiming Mouse Weight, etherization takes the tumor of each group of mice, weighs and heavily represents the work of compound with tumor
Property, data list table 3 in.Result shows that the tumor of 1 μm ol/kg Pro-Ser treatment mice is heavily significantly less than saline therapy
The tumor weight of mice, Pro-Ser shows definite anti-tumor activity.
The table 3Pro-Ser impact on the tumor weight of S180 tumor-bearing mice
N=15；A) with normal saline than p ＜ 0.01.
Embodiment 7 evaluates the thrombolysis activity of Pro-Ser
1) carry out anaesthetizing (6mL/kg abdominal cavity) with 20% urethane solution by body weight 250 ± male SD rat.Postanesthetic greatly
Mus is fixed on Mus plate, separates right carotid, presss from both sides bulldog clamp in proximal part, and proximal part and distal end pass respectively
Enter surgical thread, insert at distal end and take blood vessel, unclamp tremulous pulse and grip about 1mL arterial blood.Rapidly arterial blood is injected into
Vertical makes in bolt pipe (long 16mm, internal diameter 2.5mm, external diameter 5mm, with 1mL EP pipe base at the bottom of pipe), (note
Meaning can not have bubble) each make in bolt pipe injection 0.1mL rat artery blood, in pipe, it is rapidly inserted into thrombosis fixes
Bolt (long 20mm), blood coagulation 40min, uses acupuncture needle removal of thromboses, weighs thrombus weight.
2) bypass intubates and is made up of three parts, and wherein stage casing is polyethylene rubber tube, long 60mm, internal diameter 3.5mm, and two ends are identical
Polyethylene tube, long 100mm, internal diameter 1mm, outdoor scene 2mm, one section of this pipe pulls into spike tube, the outside of the other end
Overlap a segment length 7mm, the polyethylene tube of external diameter 3.5mm.The inwall of three sections of pipes is silanization.
3) thrombosis that thrombosis wraps up is fixed bolt is placed in the polyethylene rubber tube in stage casing, the two ends of sebific duct respectively with two polyethylene
The butt end that adds be nested, fill heparin-saline solution with syringe by spike tube end.Will be filled with the physiology salt of heparin sodium
Vein on the left of the insertion of aqueous solution one end, after the other end adds the heparin sodium anticoagulant of correct amount with syringe, pulls out heparin sodium
Syringe, insert arterial end.With scalp acupuncture by normal saline (3mL/kg) or the normal saline solution of urokinase
(20000IU/kg) or the normal saline solution (1 μm ol/kg) of Pro-Ser is by the stage casing of shunt valve, thrust away from thrombosis solid
Determine, at the nearly vein of bolt, to open bulldog clamp, make blood flow pass through bypass duct and flow into the moment of vein for circulating from tremulous pulse
Initial time, is injected into the liquid in syringe in blood (about 6min) slowly, makes normal saline, urokinase,
Pro-Ser passes through blood circulation, by the sequential action of vein-heart-tremulous pulse to thrombosis.Take out with thrombosis after 60min
Bolt, dip in floating blood, record weight.Thrombolysis activity is represented with thrombosis loss of weight.Data list table 4 in.Result shows,
The thrombosis loss of weight of Pro-Ser treatment rat is significantly greater than the thrombosis loss of weight of saline therapy rat, and Pro-Ser shows definitely
Thrombus dissolving activity.
The thrombolysis activity of table 4Pro-Ser
N=10；A) with normal saline than p ＜ 0.01.
Claims (6)
1.Pro-Ser。
2. the preparation method of the Pro-Ser of claim 1, the method includes:
(1) under the catalysis of DCC, HOBt, Boc-Pro-Ser-OBzl is synthesized；
(2) Boc-Pro-Ser-OBzl changes into Pro-Ser-OBzl in 4N HCl/EA；
(3) Pro-Ser-OBzl is at H2Pro-Ser is generated under Pd/C catalysis.
3. the Pro-Ser of claim 1 application in preparing antitumor drug.
4. the Pro-Ser of claim 1 application in preparing analgesic.
5. the Pro-Ser of claim 1 application in preparing thrombolytic drug.
6. the Pro-Ser of claim 1 application in preparing anti-inflammatory drug.
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| CN201510351774.3A CN106317172A (en) | 2015-06-23 | 2015-06-23 | Pro-Ser, and synthesis, activity and application thereof |
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|---|---|---|---|---|
| US4416871A (en) * | 1978-07-10 | 1983-11-22 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibition by peptides of tolerance to and physical dependence on morphine |
| CN1763082A (en) * | 2005-09-27 | 2006-04-26 | 南开大学 | Screening and authentication of polypeptide binding specificly to tumour tranferring cell |
| CN1876676A (en) * | 2005-06-09 | 2006-12-13 | 南京大学 | Antineoplastic oligopeptide and its preparation method and application |
| CN101217971A (en) * | 2005-07-05 | 2008-07-09 | 比奥滕普特公司 | Treatment of tumors |
| CN103665106A (en) * | 2012-09-20 | 2014-03-26 | 天津嘉宏科技有限公司 | Antineoplastic polypeptide and preparation method and applications thereof |
| CN104159912A (en) * | 2012-03-09 | 2014-11-19 | 森永乳业株式会社 | Dipeptidyl peptidase-iv inhibitor |
-
2015
- 2015-06-23 CN CN201510351774.3A patent/CN106317172A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4416871A (en) * | 1978-07-10 | 1983-11-22 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibition by peptides of tolerance to and physical dependence on morphine |
| CN1876676A (en) * | 2005-06-09 | 2006-12-13 | 南京大学 | Antineoplastic oligopeptide and its preparation method and application |
| CN101217971A (en) * | 2005-07-05 | 2008-07-09 | 比奥滕普特公司 | Treatment of tumors |
| CN1763082A (en) * | 2005-09-27 | 2006-04-26 | 南开大学 | Screening and authentication of polypeptide binding specificly to tumour tranferring cell |
| CN104159912A (en) * | 2012-03-09 | 2014-11-19 | 森永乳业株式会社 | Dipeptidyl peptidase-iv inhibitor |
| CN103665106A (en) * | 2012-09-20 | 2014-03-26 | 天津嘉宏科技有限公司 | Antineoplastic polypeptide and preparation method and applications thereof |
Non-Patent Citations (2)
| Title |
|---|
| AUBRY A, ET AL.: "Backbone side chain interactions in peptides. I. Crystal structures of model dipeptides with the Pro-Ser sequence.", 《INT J PEPT PROTEIN RES.》 * |
| 吴梧桐: "《生物化学》", 31 January 2010, 中国医药科技出版社 * |
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Application publication date: 20170111 |